Molecularly targeted agents against receptor tyrosine kinases (RTK), particularly the antiangiogenic agents (AAs), have caused a paradigm shift in cancer chemotherapy. These agents target tumor angiogenic mechanisms (sprouting of new blood vessels) that are absent in normal cells (except wound healing, menstrual cycle and pregnancy) but are vital for tumor growth and metastases. Angiogenesis pathways are redundant and multi-targeted AAs are necessary to abrogate angiogenesis. AAs are mainly cytostatic and arrest tumor growth but do not kill tumors. Thus combinations of AAs and cytotoxic agents have shown significant promise, and hundreds of such clinical trials attest to their clinical relevance. Pharmacokinetic differences of two or more drugs, drug-drug interactions, overlapping toxicities, cost of multiple drugs and patient compliance are important facets of combination chemotherapy failure. For AAs in combination with cytotoxic agents there are even more stringent requirements. Some important antiangiogenic effects like tumor vascular normalization are transiently manifested and a separately administered cytotoxic agent might completely miss this transient window. Combination chemotherapy is not a new idea, what would be novel is the design of a single agent with both multiple antiangiogenic activities as well as cytotoxicity. Such single agents would circumvent the disadvantages of two or more separate agents and afford combination chemotherapy potential in single molecules. The cytotoxic effects of such "on the spot" single agents would be manifested when dictated by the antiangiogenic effects and hence would not need to be timed or be as potent (hence less toxic) as separately administered cytotoxic agents. We have recently discovered two compounds AAG14843 and AAG148311 that each inhibit VEGFR-2 and PDGFR-$, (tumor angiogenic effects) and remarkably also inhibit human thymidylate synthase (hTS) (cytotoxic effects). The inhibitory potencies are comparable to standard inhibitors of VEGFR-2 (SU5416), PDGFR-$ (DMBI) and hTS (pemetrexed, Alimta). In a COLO-205 xenograft mouse model AAG14843 significantly decreased tumor growth, liver metastases and blood vessels in the primary tumor compared to control. The Specific Aims are: 1.) to synthesize analogs of AAG14843 and AAG148311 to provide a structure-activity relationship (SAR) study, 3D QSAR and to optimize inhibitory activity against VEGFR-2, PDGFR-$ and hTS and antitumor activity. 2.) To test analogs from Specific Aim 1 against EGFR, VEGFR-1 and 2, PDGFR-$, P13K, FLT3, A431 cells, hDHFR, hTS and in the CAM assay. 3.) To evaluate in vivo toxicity, antitumor activity, metastases and antiangiogenic activity of AAG14843 (in other xenograft models), AAG148311 and three additional analogs identified from Specific Aims 1 and 2 in tumor mouse models. This study will afford a SAR and agents with optimized attributes of AAG14843 and allow the selection of agents to be developed for monotherapy, in combination with other agents and/or radiation for clinical use with greater efficacy and reduced toxicity than combinations currently in use.